University Of Wisconsin-Madison

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Filamentous fungi are a major source of valuable natural products (e.g. antibacterial penicillin, the immunosuppressant cyclosporin, the cholesterol-lowering drug lovastatin, the fungicide azoxystrobin and the pesticide paraherquamide). Yet despite progress in genomic sequencing and the characterization of large numbers of fungal NPs, the identification of small molecules with genuinely new structures and activities has not kept pace with genome sequence. These key gaps are a consequence of current bioinformatic and genome mining procedures which are biased towards locating well-characterized classes of NPs, which follow the assumption that all genes important for synthesis of any particular NP will be clustered and lack consideration of how fungal ecology can inform chemical synthesis. We have addressed these challenges by developing the first genome-mining pipeline capable of identifying the new widespread chemical class of natural products in fungi, the isocyanides and uncovering the unexpected role of copper in regulating both isocyanide synthase (ICS) biosynthetic gene cluster (BGC) expression and compound production. To continue these advances, here we focus on three key areas of investigation including (i) elucidating products of ICS BGCs containing genes encoding unusual enzymatic features unique chemistries and/or target proteins, (ii) examining the hypothesis that isocyanides direct microbiome composition dependent on metal concentrations and (iii) exploring the potential of computational innovation to significantly advance an understanding of the foundations of fungal NP logic. Overall, this work will advance the field of NP discovery in new directions that includes promoting the chemistry and ecology of the poorly understood isocyanide NPs, dissecting consequences of NP elaboration on microbiome composition and aligning molecular and chemical proficiencies with computational innovations for uncharted NP discovery routes. Using molecular, chemical, ecological and computational tools, we are poised to uncover fundamental questions in complex fungal networks governing NP synthesis. Better understanding of these mechanisms is critical to elucidating NP classes with specific biological roles and, ultimately, to provide knowledge to address escalating direct and indirect challenges confronting human health worldwide.

NIH Research Projects · FY 2026 · 2024-12

Due to the high cost of insulin, over 1 million individuals in the United States skip insulin doses to save money, increasing their risk of avoidable diabetes-related complications and mortality. In a landmark policy change, the Inflation Reduction Act capped out-of-pocket costs for insulin at $35 per 30-day supply for Medicare beneficiaries. Little is known about the cap’s impacts on insulin access and health outcomes for people who use insulin, including existing disparities by race/ethnicity and income. Understanding the impacts of the cap is necessary to inform future policy to ensure access to insulin and other potentially life-saving drugs for all patients. The long-term goal is to identify policy solutions to increase the affordability of insulin for everyone and thereby reduce disparities in avoidable diabetes-related hospitalizations and mortality. The overall objective of this project is to measure the effect of the Inflation Reduction Act’s cap on insulin out-of-pocket costs on insulin access and health outcomes, including changes in disparities by race/ethnicity and income. The general hypothesis is that the Inflation Reduction Act cap improved insulin affordability, reduced insulin rationing, and improved health outcomes while reducing disparities, but may also have had unintended consequences relevant to insulin access such as higher Part D plan premiums or fewer insulins covered. The objective will be achieved via three specific aims: (1) Evaluate the impact of the Inflation Reduction Act cap on out-of-pocket costs for insulin, insulin use, glycemic control, and health care outcomes among Medicare beneficiaries; (2) Measure heterogeneity in the impact of the Inflation Reduction Act cap on out-of-pocket costs for insulin, insulin use, glycemic control, and health care outcomes by race/ethnicity and income; (3) Assess the link between the Inflation Reduction Act cap and changes in the standalone Part D plans serving insulin users, including increases in premiums, fewer insulin products covered, or plans exiting the market. Aims 1 and 2 will be achieved by comparing changes in outcomes between insulin users who were affected and unaffected by the policy using nationwide Medicare data and a large database of electronic medical records. Aim 3 will be achieved by measuring changes in the extent to which Part D plans with many insulin users increase their premiums, decrease the number of covered insulins, or exit from the Part D market. At the successful completion of this research, the expected outcomes are the identification of mechanisms through which out-of-pocket caps impact access to insulin and health outcomes. The project is innovative in its focus and approach: Substantively, this will be the first comprehensive analysis of the Inflation Reduction Act’s cap on out-of-pocket costs for insulin including both intended and unintended consequences. Methodologically, the project includes a novel analysis of electronic health records to measure changes in clinical outcomes. These results will provide a strong basis for the future development of policy aimed at improving insulin access, which is expected to have a significant impact on avoidable diabetes-related complications.

NIH Research Projects · FY 2026 · 2024-12

Abstract The brain is structured by experiences through a process called neuroplasticity. Neuroplasticity is highest in early life, during the phase of rapid brain growth. During this growth spurt period, the brain is also exceedingly vulnerable to toxicity of environmental influences. Hypoxia, trauma, infections, medications that influence activity levels of neuronal networks can trigger cell death, and impair the formation of new cells (neurogenesis) and neuronal connections. This period in humans expands from the third trimester of pregnancy to the 3rd year of life. Noninvasive brain stimulation (NIBS), in particular transcranial direct current (tDCS) stimulation, is increasingly being used to promote neuroplasticity and repair in the human brain. tDCS has been used in clinical trials in adults and children. Substantial benefits have been demonstrated in the treatment of neurologic and psychiatric disorders in different age groups. tDCS is considered safe and well tolerated. Utilization of NIBS interventions in infancy and early childhood may bear the greatest potential for improving neurologic and neurocognitive outcomes, given the enormous ability of the brain to reorganize at that stage. But, we do not know whether tDCS can be safely administered to infants and young children. Research in animal models on the potential toxic effect of NIBS on very young brains, in particular during the brain growth spurt period, has been very limited. Thus, there are justified concerns that modulation of brain activity at that stage might be harmful. These concerns pose ethical barriers to clinical trials utilizing tDCS and other NIBS interventions in infancy and early childhood. Consequently, there is a great need for preclinical research in appropriate animal models that will explore toxic thresholds of NIBS in developing brains. Here we propose to investigate the nature of and the thresholds for neurotoxic, gliotoxic, and neuroinflammatory effects of tDCS in developing guinea pigs. We will use guinea pigs at ages 1-30 days, which is considered the age equivalent of 10-30-month-old humans. We hypothesize that (a) tDCS will cause dose-dependent toxicity and neuroinflammation in infant guinea pig brains and (b) thresholds for neurotoxic and neuroinflammatory responses to tDCS will increase as the brain matures. To address these hypotheses, we will first expose 1-day- old guinea pigs to 5 serial daily sessions of tDCS at different current intensities and will computationally model generated electrical fields using head and brain models generated from MR- and micro-CT images. To identify toxic thresholds at this age, we will analyze the brains for signs of cell death, alterations of dendritic morphology and inflammation at different stimulation current intensities. We will then investigate toxic thresholds of tDCS at different ages. For that, we will perform experiments on 15 and 30-day-old guinea pigs. Using computational modeling at each age, we will be able to determine whether and how the vulnerability of brain tissue to comparable electrical fields changes as the animals mature. These studies will generate valuable knowledge which will help define tDCS doses that are safe to use in infants and young children.

NSF Awards · FY 2024 · 2024-12

The broader impact/commercial potential of this I-Corps project is the development of a ferroelectric membrane that serves as an essential component in all types of rechargeable metal ion batteries, offering critical improvements in stability and cost-effectiveness. The battery industry, especially small to medium sized battery manufactures specializing in energy storage systems, are facing critical issues related to dendrite growth and short circuits, which can lead to reduced battery performance, capacity loss overtime and safety concerns. Overcoming dendrite growth is critical for advancing battery technology to remain competitive in the evolving energy storage landscape. The technology directly addresses these pressing challenges faced by them, specifically mitigating the issues of poor stability and high costs. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of the technology. The solution is based on the development of mesoporous polymeric ferroelectric membranes, introducing a groundbreaking separator technique for metal ion rechargeable batteries. The proposed innovation lies in a ferroelectric membrane designed to self-responsively counteract the electric field from metal dendrites, a critical issue that limits the batteries' lifetime and charging rate. While current solutions primary concentrate on novel electrode materials and electrolytes to mitigate dendrite growth, the approach presents a universal solution from the separator standpoint. This solution not only delivers similar enhancements in battery performance but also proves to be more cost-effective. The ferroelectric membrane can provide an over 20% battery stability and performance increase compared to conventional separators, and offers adaptability, as it can be tailored to suit various battery systems with ease. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-12

This project aims to advance Artificial Intelligence (AI) by investigating the mathematical foundations and practical applications of deep learning models, which encompass broad class of neural network methods. The focus is on understanding the properties of neural networks that are trained on large datasets, investigating how these properties enable networks to model complex data distributions and capture intricate dependencies within the data. By analyzing the progressively refined data representations that emerge during training, the project seeks to uncover the principles underlying the ability of neural networks to map and represent complex information. This research promises to enhance our understanding of network architectures and their capabilities, with potential applications in areas such as image processing and natural language understanding. Moreover, the project will train the next generation of AI researchers. Through hands-on involvement in cutting-edge work, students will gain invaluable experience and develop the innovative thinking needed to tackle future challenges. Ultimately, this effort not only builds a skilled workforce but also contributes to the broader goal of advancing AI technology to better interpret and interact with the world. The goal of this project is to deepen the understanding of the deep learning models that underpin modern AI systems by exploring vector-valued, multi-output mappings, compositional function spaces, and the inner workings of transformer architectures. Bridging theoretical insights with practical applications, the project aims to develop novel network architectures, regularization strategies, and training methodologies to improve the performance and generalization capabilities of neural network models. Central to this effort is the study of compositional function spaces and the progressively refined data representations that emerge during training. This includes investigations into both low-dimensional settings, such as implicit neural representations for images and continuous fields, and high-dimensional domains in computer vision and language modeling. A particular focus will be on transformer architectures, with the goal of understanding the evolution of data representations within these models and uncovering task-specific representations enabled by novel training techniques. By examining the function spaces and mappings characteristic of deep learning models, this research seeks to uncover new foundational principles of data representation and processing. These insights promise not only to advance our theoretical understanding of deep learning mechanisms but also to enable innovative AI applications across a wide range of fields. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-12

Proteins are the catalytic agents in the cell and carry out most cellular reactions. Control of the abundance or activity of cellular proteins can be used to modify cellular pathways and, by extension, control the health and viability of an organism. While systems for targeted destruction of proteins of interest are available for research and therapeutics in animals, very few tools exist to control protein abundance in plants. Instead, plant scientists are currently reliant on methods that regulate protein abundance at the level of mRNA expression, which are inherently slow. This research will enhance the capabilities of a recently developed tool to control protein degradation in plants called E3 DART, thus providing the opportunity to control the abundance of a protein target at the protein level. Specifically, this work will expand the mode of activation of E3 DART and widen its applicability to multiple plant species of research and commercial importance. The Broader Impacts of this work include its intrinsic merit as the optimized tool will enhance fundamental plant biology research and may be deployed in the future for applied agronomic innovations. Agronomic industry innovations that could benefit include developing novel herbicide resistance traits, engineering pathogen resistance by degrading pathogen effectors or design of new haploid technologies for faster breeding. Additional activities include outreach and development of teaching tools for museum activities, high school and/or undergraduate courses, and plasmid designs and plant lines deposited in public repositories. The research team will continue to mentor young scientists to develop a strong workforce in STEM. Inducible protein degradation systems are an important, but untapped resource for the study of protein function in plant cells. The recently developed E3-targeted Degradation of Plant Proteins (E3-DART) is a protein degradation system based on the activity of a Novel E3 Ligase (NEL) from Salmonella. The goals of this work are to optimize the E3 DART system such that it can be chemically controlled and, combined with other recombinant strategies, used in proof-of concept experiments to test the function of specific endomembrane proteins. This complementary set of tools, which are lacking in model plant systems, will provide deeper insights than previously possible into the highly dynamic, temporal, and spatial molecular mechanisms of organelle biogenesis and endomembrane trafficking. The specific aims of this research are to: 1) Develop a ligand-inducible E3-DART system; 2) Control E3-DART activity with novel recombinant tools; and 3) Develop proof-of-concept methodology with E3-DART to study endomembrane protein function and synchronized secretory protein trafficking. A robust system to control protein degradation will have a significant impact on plant biology. Key for the development of such systems is to engineer plant lines in which the degron-tagged protein of interest functionally complements a mutant, and the E3 DART activity and target protein degradation are controlled in a tunable and reversible manner. Such capability will allow for future characterization of the function of essential proteins involved in dynamic cellular processes in plants in ways not achievable with existing tools. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-12

High-grade serous ovarian cancer (HGSOC) has a five-year survival rate of <50% due to the rapid and extensive metastasis observed in patients. Metastasis in HGSOC can occur through transcoelomic spread, in which tumor cells detach, float through the peritoneal fluid, attach to the peritoneal cavity-facing surfaces of tissues, and establish new tumors. Rapid metastasis is supported when the primary tumor sends signals that convert healthy tissues to a site that is more hospitable for metastasizing tumor cells; the altered tissue is called a premetastatic niche (PMN). Determining what is different in the PMN, how this difference supports metastasis, and the mechanisms responsible for these alterations could lead to therapeutic approaches that slow or stop metastasis. The most common site of distal metastasis in HGSOC is the omentum, a visceral fat deposit. We examined the omentum from healthy females and patients with early-stage HGSOC (prior to metastasis to the omentum). Our preliminary data demonstrated that collagen type I (Col I) density, cellular fibronectin (cFN) density, transglutaminase-2 (TGM2) cross-links, and collagen fiber thickness were all significantly increased in the omentum of patients with early-stage HGSOC. We hypothesize that these changes in the ECM of the omentum result in a PMN that supports tumor progression through direct effects on tumor cell adhesion, invasion, migration, proliferation, and apoptosis, and that the observed ECM changes result from preconditioning of this niche by factors in the peritoneal fluid. We will test this hypothesis across three Aims: 1) Examine the direct effect of ECM alterations observed in the HGSOC PMN on tumor cells. 2) Determine the impact of ECM alterations in the PMN on HSGOC metastatic seeding and expansion. 3) Elucidate mechanisms by which the ECM of the omentum is converted to that of the PMN. These studies will be conducted by an inter-disciplinary team with expertise in ovarian cancer from basic science and clinical perspectives, in vitro culture system development, in vivo mouse models, ECM, biomaterials, and exosomes. Completion of these Aims will determine how changes in the ECM that precede tumor cell arrival influence metastasis. Additionally, we will determine which factors in the peritoneal fluid regulate these changes in the ECM to identify future therapeutic strategies or biomarkers for patients at high risk.

NIH Research Projects · FY 2025 · 2024-12

PROJECT SUMMARY/ABSTRACT Abstract: High-risk polymorphisms for diabetes account for only a fraction of the overall disease heritability, implying significant conditional dependencies regulate the influence genes exert on islet function. Machine learning (ML) methods can identify such dependencies from omics data. I will apply machine learning (ML)- based methods to identify conditional dependencies regulating islet function. I will derive and validate ML models predicting islet function from proteins measured in islets of Diversity Outbred (DO) mice (AIM 1). For models with high predictive accuracies in both mouse and human data, I will use the proteins’ model weights as meta-traits to identify genomic regions altering those proteins’ influence on insulin secretion. One protein my ML models and prior studies predict to alter insulin secretion is transketolase (TKT), an enzyme in the pentose shunt. Knockdown of TKT in mouse and human islets increases insulin secretion. Since the pentose shunt is not thought to be a key pathway in β-cells, I will characterize a novel function of TKT and will use ML to determine its conditional dependence on other proteins. Using constructs restricting TKT activity and localization, I will establish whether TKT’s enzymatic activity and nuclear localization are required for its suppression of insulin secretion (AIM 2). Using these constructs, I will identify TKT’s binding partners in the cytosol and nucleus by immuno-precipitating the compartment-restricted TKT followed by mass spectrometry (IP/MS), filtering for non-specific proteins using ML-based likelihood scoring of the identified proteins. Collectively these studies will provide novel models for interrogating protein conditional dependencies in islets and identify partners for TKT that could offer potential new drug targets. Training plan/career goals: My career goal is to become an independent NIH-funded investigator at a top-tier research institution. Identifying conditional dependencies in complex data is key for understanding metabolic disorders. My mentors, Drs. Craven and Smith are experts in ML and proteomic analyses, respectively. Other advisors have specific areas of focus tailored to sub-components of the grant’s respective aims. Implementing ML in biological data is potentially powerful but not straightforward. The proposed courses and workshops and working directly with my mentors’ labs will provide conceptual and programmatic background for implementing these methods. UW-Madison is an ideal location for this because of the strong support for learning and applying new computational methods. In particular, the Center for High-Throughput Computing offers free 24/7 access to clusters of high-end processors and the necessary memory and professional support for working with these complex data. They also offer training for computing languages in which many of these newer methods are implemented. Collectively, the proposed project training will enable me to identify conditional dependencies for metabolic regulators beyond the specifics of these studies and provide an essential foundation for me to transition to independence.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY About 600,000 people are released annually from state and federal prisons and millions more from local jails. Around half of these individuals have a history of mental illness, yet the majority fail to receive mental health treatment upon reentry. Mental health difficulties impede successful reentry outcomes such as stable housing, employment, and positive relationships, perpetuating generational cycles of incarceration and exacerbating health disparities that disproportionately affect communities of color. The long-term goal of this research is to integrate evidence-based mental health support into existing reentry programming to promote healing from trauma and facilitate successful community reintegration. The overall objective of this project is to provide preliminary feasibility, effectiveness, and implementation data on an evidence-based mental health curriculum adapted with and for formerly incarcerated people. The Healthy Minds Program (HMP), an app-based intervention with demonstrated efficacy for reducing anxiety and depression, promotes four components of well-being: Awareness, Connection, Insight, and Purpose. In collaboration with community partners and formerly incarcerated people, this Type 1 Hybrid study will create an in-person adaptation of HMP for reentry (HMP-R) and provide preliminary data in support of a future multi-site effectiveness trial through two specific aims: 1) Adapt the Healthy Minds Program with and for formerly incarcerated individuals; 2) Establish feasibility, acceptability, adherence, and preliminary effectiveness of HMP-R. Aim 1 will utilize the evidence- based ADAPT-ITT model to adapt HMP using a trauma-informed approach for in-person delivery by a mindfulness instructor and a formerly incarcerated co-facilitator. The first draft of HMP-R will be revised with input from formerly incarcerated community advisory board members, content experts in meditation practices for groups disproportionately impacted by incarceration, and professionals working in reentry services and support. The curriculum will be further refined through an iterative process of field testing and feedback from formerly incarcerated community members. Aim 2 involves a pilot randomized controlled trial of HMP-R vs. waitlist control in 60 individuals released from prison or jail in the previous year. A convergent mixed methods design will be used to integrate qualitative and quantitative data on feasibility, acceptability, and adherence for HMP-R and associated assessment procedures. Preliminary effectiveness outcomes will include increases in questionnaire measures of Awareness, Connection, Insight, and Purpose (target engagement) and associated reductions in psychological distress (clinical outcome). This project is innovative in providing a strength-based approach to supporting mental health and well-being during reentry, an approach that is grounded in the experiences and wisdom of those with lived experiences of incarceration. This project is significant because cultivating skills that facilitate well-being can boost mental health and increase the potential for successful reentry, community reintegration, and the reduction of mental health disparities.

NIH Research Projects · FY 2026 · 2024-12

The mammalian intestinal tract is inhabited by trillions of bacteria. Approximately half of the bacteria contain viral DNA—prophages—in their genome. Nearly exclusively studied in pathogens, the long-term co-evolutionary relationship between these so-called lysogenic bacteria and their prophages has led to beneficial and detrimental consequences to the bacterial host. However, we know virtually nothing to what extent, and by which mechanisms, prophages modulate the metabolism of a probiotic gut symbiont. Until we have filled these voids in our knowledge base, we will not be able to develop rational selection approaches for (engineered) probiotics and, consequently, the impact of probiotic-encoded prophages on human health will be vastly overlooked. Our long-term goal is to gain mechanistic insight into the interplay between probiotic bacteria and their prophages. The objectives of this research program are (1) to elucidate the mechanism by which prophages modulate the production of a probiotic effector molecule, reuterin, in the probiotic gut symbiont Limosilactobacilus reuteri; and (2) to determine the ecological ramifications of phage-mediated reuterin production in vivo. The overarching hypothesis is that prophage-mediated regulation of cellular metabolism promotes probiosis. We base our hypothesis on a synthesis of published findings and exciting preliminary data, which are that (a) the pdu operon produces the broad-spectrum antimicrobial reuterin; (b) reuterin is not detected upon deletion of both prophages; (c) reuterin production is restored in the prophage-deletion strain by expression of a single prophage-derived protein, hereafter referred to as reuterin-modulation protein A (RmpA); (d) we established that in vivo reuterin production reduces pathogenic E. coli. The rationale of the work proposed is that its successful completion will result in a paradigm shift in our understanding of how prophage-microbe interplay can be intertwined with human health. To accomplish the objectives for this project, we will pursue the following specific aims: (1) To characterize the interplay between RmpA and TpiA in relation to reuterin production; (2) To characterize RmpA and identify its interacting partners; (3) To determine to what extent prophages impact probiosis via reuterin production. This research is innovative because we apply sophisticated genome editing tools in an important gut symbiont species. Also, our research question is innovative as we expect to uncover fundamental knowledge on the mechanisms by which prophages modulate microbial metabolism in the gut ecosystem. The research is significant because its successful completion is expected to result in a paradigm shift in how we view the role of prophages in (probiotic) gut symbionts.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY The retina employs a multitude of parallel neural circuits to encode the many aspects of vision. At all light levels, and in all circuits, cellular noise threatens the accurate encoding of visual stimuli. To combat noise, the retina uses circuit and synaptic mechanisms to amplify signal and filter out noise. Two examples of this are nonlinear convergence, the filtering and subsequent pooling of many neural signals into one neuron, and divergence, the spreading of a single signal into many neurons. Two important neural circuits that emphasize the presence, or lack, of circuit mechanisms, are the rod pathway and foveal midget pathway, respectively. The rod pathway uses high degrees of nonlinear convergence to amplify single photon signals enabling vision in extremely dark environments. The foveal midget pathway encodes hyperfine spatial detail by doing away with circuit mechanisms such as convergence and divergence in exchange for 1:1 connections between neurons. The relative density of neurons in the retina varies across retinal regions influencing the degree of convergence/divergence, and thus the magnitude of noise in neural circuits. While rod pathway sensitivity has been studied in peripheral macaque retina, where convergence is high and cell density is low, the question of how cellular connection augments rod pathway sensitivity across regions has yet to be answered. This is all the more salient due to recent literature which has pointed to regions with lower convergence but higher cell density as having the highest dim light sensitivity. My project proposes to look at single cell metrics of rod pathway sensitivity in these retinal regions. The foveal midget pathway is capable of responding to minute variations in contrasts to encode the fine spatial detail of our foveal vision. It manages to do so in the absence of convergence or divergence to amplify signal. The question remains: “how has signal processing in the foveal midget pathway adapted to a lack of key circuit mechanisms?” My project proposes to determine if regularity in synaptic release is the mechanism by which the foveal midget circuitry encodes information in the absence of prominent circuit mechanisms like convergence and divergence. This project will bridge the gap between our mechanistic understanding of rod pathway sensitivity and the regional sensitivity indicated by psychophysical studies – providing a more complete understanding of how varied cellular connectivity affects our most sensitive retinal pathway. Given the importance of our high-acuity foveal vision and the relative lack of understanding of foveal signal processing, this project will determine key mechanisms enabling foveal vision to operate with hyperfine spatial acuity. The pursuit of this project will enhance our understanding of how the neural code changes as a consequence of varied cellular connectivity.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT The goal of this study is to determine the feasibility of a proposal to determine the incidence, breadth of clinical manifestations, course and outcome of Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorder Associated with group A Streptococcus (PANDAS) in a geographically and economically diverse population of children in the US. PANS is a relatively newly described clinical problem characterized by the acute onset of either obsessive-compulsive disorder (OCD) or food restriction (or both) plus two of 7 other neuropsychiatric/behavioral issues in children. PANS may be triggered by infectious or non-infectious stimuli. When Group A streptococcus (GAS) is the instigator event, it is referred to as PANDAS. The two cardinal features of PANDAS are tics and OCD. Intrinsic to both syndromes is the extremely acute onset of symptoms. Knowledge of the incidence, breadth, course and outcome of PANS/PANDAS has been hampered by the absence of both a biomarker and a registry. Most studies of clinical presentation have been retrospective and emerged from research/referral centers which provide an unavoidably skewed picture of the most severe cases which are catastrophic but may not be representative. In Specific Aim 1a we will demonstrate the feasibility of the prospective identification, enrollment and clinical description of children with PANS and PANDAS in geographically distinct populations of children in the US in order to determine the incidence, spectrum and course of these disorders. To accomplish this aim we will identify 2 different health systems which include a primary care population of children with an electronic health record (EHR) that is comprehensive. Using a combination of a ‘best practice alert’ and a tailored algorithm, pertinent EHRs will be reviewed every weekday. Applying stringent clinical criteria, we will enroll consecutive children with new and abrupt onset of tics, OCD or food restriction who fulfill the definitions for PANDAS/PANS and follow them. We will successfully enroll 85% of the children meeting criteria. In Specific Aim 1b we will demonstrate that GAS is an instigator event in at least 65% of cases of PANS. In Specific Aim 2 we will determine the feasibility of studying the course and outcome of children with PANS/PANDAS enrolled prospectively. Children identified in Aim 1 will be evaluated at baseline and every 6 months with the Child-Yale Brown Obsessive Compulsive scale (CY-BOC) if the child has OCD, the Yale Global Tic Severity Scale (YG- TSS) if the child has tics, the Clinical Global Impairment score (CGIS) and the Child Global Assessment Scale (CGAS). The compilation of these scales will allow classification of at least 85% of children at outcome as being in remission, or having mild, moderate or severe disease. This rigorous, prospective, observational study will demonstrate the feasibility of this approach in preparation for a larger multicentered study with more prolonged follow-up. A comprehensive understanding of the entire scope of illness will facilitate appropriate allocation of therapeutic resources and set the stage for randomized clinical trials to assess treatment modalities.

NIH Research Projects · FY 2026 · 2024-12

Project Summary/Abstract Membrane fusion is a fundamental process in eukaryotic cells, yet the precise molecular mechanism(s) by which proteins catalyze the merger of lipid bilayers has yet to be elucidated. We address the nanomechanics of membrane fusion reactions by focusing on the fusion of synaptic vesicles (SV) with the presynaptic plasma membrane in neurons. This fusion event results in the release of neurotransmitters and thus underlies neuronal function. In synapses, interactions between v- and t-SNAREs initiate the first step in the fusion reaction: the formation of the fusion pore. These are short-lived, channel-like structures that represent the first aqueous connection between the lumen of secretory vesicles and the extracellular space. To understand the biophysics of the fusion reaction, it is imperative to address the dynamics of SNARE complexes and the fusion pores that they form. In project 1, we leverage a novel system, innovated via our current R35 (that ends soon), that enabled the first µsec measurements of single, recombinant, reconstituted fusion pores. In this system, a fusion pore forms between a v-SNARE-bearing nanodisc (ND) and a black lipid membrane (BLM) that harbors t-SNAREs (ND-BLM system). The rigid membrane scaffold around the ND limits pore dilation and thus holds pores in a nascent state. Importantly, pores are interrogated electrophysiologically, and the high sampling rate revealed dynamics that had not been previously observed. This system enables us to quantitatively measure opening and closing rates, and to estimate pore size via unitary pore currents. We will continue this line of study, to: address the regulation of fusion pores by accessory proteins, relate structural transitions in SNAREs with kinetic transitions in fusion pores, create progressively larger NDs to quantitatively study the pore dilation step, determine the molecular basis for the cation selectivity of pores, and address the activation energy for pore opening. In project 2, we will determine the structure of fusion pores formed between v- and t-SNARE- bearing NDs, via cryo-EM. For this work, we utilize DNA nanostructures to obtain the required sample homogeneity needed for single-particle averaging. These DNA nanostructures will also be used to dictate the organization of SNARE proteins, so that we can infer the structure of the fusion pore via functional assays. Finally, in project 3, we extend our studies of fusion pores to study the modes of SV release in neurons. We will develop robust, rigorous, optical approaches to “size” the SV fusion pore using dyes with different radii. This work will directly address the controversy of whether SVs always undergo full fusion collapse (FFC), or if they sometimes undergo kiss-and-run (K&R) exocytosis in which the fusion pore closes prior to dilation and merger. K&R exocytosis, through a non-dilating fusion pore, would hinder glutamate efflux; this would have a major impact on the post synaptic response to dramatically impact information flow in the nervous system. In summary, our goals are to understand the dynamics, and determine the structure, of the SV fusion pore, and directly address the FFC versus K&R controversy.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Quorum sensing (QS) is the process by which bacteria of the same species coordinate behavior at a high population density. In many pathogenic bacteria, QS systems are used to regulate virulence. This proposal focuses on the accessory gene regulator (agr) QS system found in the Gram-positive pathogen Staphylococcus aureus, which uses agr to regulate an arsenal of toxins and biofilm formation. Small molecules that inhibit agr QS have the potential to be used as therapeutics to combat S. aureus infection. Previous small molecules that have been reported to inhibit agr QS suffer from low potencies, poorly characterized mechanisms of action, and/or associated toxicities that render them impractical for use as chemical probes. Herein I propose to develop a new class of small molecule agr inhibitors, study their biochemical mechanisms of agr inhibition, and investigate their effects on S. aureus growth/invasion in human cells. In Aim 1, I will develop a class of potent agr inhibitors through structure activity relationship (SAR) analyses on small molecule agr modulators recently identified in our lab. I will design new synthetic routes to access the core structure of two best-in-class small molecule inhibitors that represent the most potent small molecule inhibitors of S. aureus agr QS to date. These redesigned syntheses will enable facile functional group variation for the delineation of SARs and allow for installation of reactive groups for use in photoaffinity probes. My primary goals will be to improve compound potency, membrane permeability, solubility, and stability. In Aim 2, I will characterize the mechanisms of agr inhibition by these new small molecule scaffolds. Almost all known agr inhibitors target autoinducer (AIP) binding to the transmembrane histidine kinase AgrC or intracellular response regulator AgrA:DNA binding. Elucidating the mechanisms of agr inhibition by these new small molecules may provide access to chemical probes that target other components of the agr QS system. I will use a series of in vitro and cell-based assays to determine the target protein/pathway of these compounds, and photoreactive probes to characterize ligand binding sites on these targets. In Aim 3, I will explore the effects of these small molecule agr inhibitors on S. aureus growth/invasion in mammalian cells. S. aureus can use agr to evade the immune system and cause persistent infection by infiltrating a wide range of human cell types. Macrophage invasion assays will be used to evaluate the cell permeability of the lead small molecule agr inhibitors developed in Aims 1 and 2, their ability to be phagocytosed, and whether inhibition of agr QS by these compounds decreases macrophage invasion by S. aureus. Lastly, the inhibition/dysfunction of agr QS may enable the development of S. aureus small colony variants (SCVs) that are less likely to evoke an immune response. The ability of these small molecules to induce transition to SCVs by agr inhibition will be investigated in Aim 3. Such experiments are yet to be explored and could yield a new route to study infection progression. Together these three Aims will provide valuable chemical tools and new insights for the study of agr QS.

NIH Research Projects · FY 2026 · 2024-11

Abstract This new R01 proposal explores novel mechanisms underlying RNA regulation in heart failure (HF), a major global health concern with high morbidity and mortality. The PI is an advanced HF cardiologist, who studies transcriptional regulation in HF and myocardial recovery. Based on data generated with support from the NIH K08 program, we will explore new roles for DEAD-box RNA helicase 5 (Ddx5) in cardiac homeostasis and disease. Ddx5 regulates virtually every step of RNA metabolism including alternative splicing, mRNA stability, ribosome biogenesis, and translation, but the cardiac functions of Ddx5, the most highly expressed DEAD-box RNA helicase in the human heart are unknown. Preliminary data from our laboratory showed Ddx5 was downregulated in chronically failing human hearts and in hypertrophic mouse hearts. We demonstrated that mice with cardiomyocyte-specific Ddx5 deletion (Ddx5-cKO) developed progressive lethal cardiomyopathy associated with aberrant RNA splicing in key sarcomere genes, marked downregulation of dystrophin mRNA and protein, and a significant reduction in cardiomyocyte contractility. Co-immunoprecipitation experiments identified an interaction between Ddx5 and hnRNP H1 splicing factor in human and mouse cardiomyocytes. We propose to test the novel hypothesis that dysregulation of Ddx5 signaling contributes to the pathogenesis of HF by disruption of RNA splicing and downregulation of mRNA networks that are critical for cardiomyocyte function. In Aim 1, we will determine the mechanisms by which Ddx5 regulates RNA splicing in cardiomyocytes. Using in vitro splicing reporter assays, we will test whether the RNA splicing function of Ddx5 depends on target intronic sequences and/or cooperation with hnRNP H1. We will generate mutant Ddx5 constructs to determine which domains are critical for splicing regulation in vitro. eCLIP-sequencing and RNA immunoprecipitation-qPCR will identify direct RNA splicing targets of Ddx5 in cardiomyocytes. In Aim 2, we will elucidate the mechanisms by which Ddx5 regulates cardiomyocyte contractility using luciferase assays, ChIP-qPCR, and proximity labeling mass spectrometry to characterize the transcriptional and post-transcriptional regulatory functions of Ddx5 in the heart. To determine whether the HF phenotype of Ddx5-cKO mice is due to dystrophin deficiency, we will attempt to rescue the phenotype in vivo using AAV-based mini-dystrophin gene therapy. In Aim 3, we will determine whether Ddx5 overexpression protects mice from pathological cardiac remodeling by subjecting cardiac-specific Ddx5 transgenic and littermate control mice to pressure overload induced by transverse aortic constriction (TAC). As an alternative in vivo Ddx5 overexpression strategy, we will assess the effects of TAC in wild-type mice treated with AAV9-Ddx5 versus AAV9-eGFP vectors via tail vein injection. RNA and protein targets of Ddx5 will be confirmed in human cardiomyocytes and heart tissue. These studies will provide new insights into RNA metabolism and Ddx5 signaling in the heart under baseline and stress conditions, with potential implications for novel therapies to treat the growing population of HF patients.

NIH Research Projects · FY 2026 · 2024-11

Abstract: Recognition of invading pathogens by the innate immune system triggers a series of signaling cascades that together program an appropriate adaptive immune response. Listeria monocytogenes is a Gram positive, intracellular pathogen that triggers robust innate immune responses upon escape from the phagosome into the host cell cytosol. Cytosolic innate immune recognition of L. monocytogenes ultimately results in priming of a robust protective immune response mediated by CD8+ T-cells. We recently demonstrated that production of the eicosanoid prostaglandin E2 following L. monocytogenes escape to the cytosol is essential for optimal CD8+ T-cell priming. How PGE2 is induced in response to cytosolic L. monocytogenes and how it subsequently promotes cell mediated immunity are currently unknown. We will take an unbiased approach to identify bacterial determinants of PGE2 induction using an established bacterial transposon mutant screen. In parallel we will use ex vivo dendritic cell-T-cell co- culture models to define the signaling pathways and cell types upon which PGE2 acts to promote CD8+ T-cell priming. Finally, using both pharmacologic agonists and antagonists as well as tissue specific PGE2 receptor knockout mice we will assess the role of specific PGE2 signaling pathways in CD8+ T- cell mediated protective immunity. Upon completion of these aims we will have identified how phagocytes produce PGE2 in response to cytosolic L. monocytogenes and will have identified bacterial mutants that induce altered levels of PGE2. We will have determined how PGE2 modulates dendritic cells and/or T-cell signaling to promote CD8+ T-cell priming and cell mediated immunity. Finally, we will have identified small molecules that improve T-cell responses in combination with L. monocytogenes-based vaccines. Future studies will focus on determining the conservation of PGE2 production as a response to cytosolic bacterial infection and whether PGE2 signaling promotes immunity in the context of L.monocytogenes stimulated anti-tumor immunity. Additional future studies will use the information generated here to determine if altering PGE2 signaling could improve the generation of CD8+ T-cells in response to other vaccine platforms such as mRNA-based vaccines.

NSF Awards · FY 2024 · 2024-10

This project aims to serve the national interest by providing research-based resources to the undergraduate STEM teaching community to advance inclusive teaching strategies, which have great potential for addressing persistent inequities found in the recruitment and retention of students with marginalized identities in undergraduate STEM education. This IUSE Institutional and Community Transformation project will work to assist those involved in instructional development in designing, implementing, and evaluating inclusive teaching programming for STEM instructors. This project holds significant importance as it has the potential to enhance the quality and quantity of faculty trained in inclusive teaching practices. This, in turn, will improve institutional and classroom climates, ultimately resulting in greater student outcomes overall, with particular emphasis on benefiting students holding marginalized identities in STEM. The goal of this project is to develop a guidebook and training for those interested in advancing inclusive teaching through STEM faculty development. The scope of the project includes three primary activities. First, the project will translate research to practice by (a) conducting additional quantitative analyses (i.e., exploratory & confirmatory factor analysis; mediated serial modeling) with data from the Inclusive STEM Teaching Project (ISTP), (b) creating the new Integrated Framework of Inclusive Teaching Development, and (c) conducting semi-structured interviews to examine the applicability of the new integrated framework. Second, the project will create the Faculty Inclusive Teaching Survey (FITS) Guidebook, which will include several elements such as validated survey constructs, key qualitative themes, validated instruments, and directions for implementation. Lastly, the project will provide training to the STEM education reform community on the FITS Guidebook at three levels: (1) short-duration workshops (level 1), (2) high-engagement workshops (level 2), and (3) workshops to reconvene level 2 attendees to share implementation experiences and make plans for future applications of the FITS materials. The project will evaluate progress and goal achievement through strategic engagement with an advisory board and data collection to inform formative improvements and capture summative impact. The project seeks to expand the field’s understanding of instructor inclusive teaching development and to provide rich and practical recommendations, instruments, and training. The project aims to increase the undergraduate STEM teaching community’s knowledge of how instructors learn to teach inclusively, including programmatic implications, and will provide research-based resources to those involved in STEM faculty development at different types of higher education institutions in the United States. Project results will be disseminated through peer-reviewed conference presentations, manuscripts, and existing NSF-affiliated networks (e.g., the INCLUDES National Network). The NSF IUSE: EDU Program supports research and development projects to improve the effectiveness of STEM education for all students. Through its Institutional and Community Transformation track, the program supports efforts to transform and improve STEM education across institutions of higher education and disciplinary communities. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-10

This project aims to serve the national interest by improving college students’ belonging and persistence in science by reimagining failure as a productive part of scientific research. To meet national needs of the future, the United States must increase the production of STEM college graduates and draw on a broader range of talent, particularly from among communities historically underrepresented in their participation in STEM courses of study. Scientists are affected by two types of failure that are natural parts of a career in science - personal setbacks and scientific failures - which influence advancement in academic and professional paths. But many students interpret a failure in college due to academic or personal struggles or due to failed experiments as an indication that they lack the ability to succeed in STEM. In reality, when students encounter learning challenges, personal roadblocks, or wrong hypotheses and failed experiments, they must tap into productive failure responses to identify support structures, figure out what went wrong, adjust their approach, and try again. Productive responses to failures can be personal, such as leveraging a growth mindset, or scientific, such as troubleshooting an experiment. By learning productive failure responses, students develop problem-solving skills, reasoning, and resilience, which strengthen a sense of belonging and lead to persistence in STEM. A better understanding of the impact of failure and approaches that de-stigmatize and normalize failure in college is important for assuring greater success and retention of diverse students in STEM. The goal of this project is to create and test a productive failure intervention that comprises a set of video interventions to address student failure responses and STEM persistence. The project scope includes developing a video-based “Productive Failure Intervention” for college STEM courses, evaluating the impact of the intervention on students’ failure responses, and then disseminating the intervention for STEM college educators. The videos would incorporate stories from successful scientists about how they leveraged productive responses when experiencing personal or scientific failures, with a set of control videos that do not address productive failure responses. After seeing videos, student’s failure responses would be measured using a survey and an impossible-to-solve video game. Students would complete the tasks as a normal course assignment and receive course credit. The intervention would be made freely available for any college instructor to incorporate into their STEM courses and also incorporated into the instructor training program for a course-based undergraduate research experience (CURE) in microbiology called Tiny Earth. Evaluation findings would be published in science education journals and presented at professional conferences. The NSF IUSE: EDU Program supports research and development projects to improve the effectiveness of STEM education for all students. Through its Engaged Student Learning track, the program supports the creation, exploration, and implementation of promising practices and tools. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-10

This project advances science and technology by addressing a societal need for developing fundamentally new techniques for better detecting brain activity. A multitude of biomedical technologies enable direct brain recording and stimulation and are central to brain research and for diagnosing and treating neurological disorders. However, current techniques are either highly invasive, require bulky transmission circuitry, or provide spatially constrained nonspecific readouts from limited regions in the brain. This hinders the ability of neurologists and neuroscientists to uncover the inner working of the brain during normal cognition and to elucidate neuropathological processes governing debilitating brain dysfunction. Discovering improved architectures for realizing extremely small and yet highly responsive electronic agents that can relay signals wirelessly and be injected safely with minimal injury across large regions of the brain can address these difficulties and transform the way we access the nervous system. This project investigates a new and effective sensing architecture that can greatly empower brain imaging by using extremely small particles composed of specialized magnetoelectric materials that respond to electric fields in tissue and used in conjunction with whole brain imaging for unprecedented detection of physiology. The project relies on state-of-the-art engineering methods to enable the optimization of synthesis and biological compatibility of the particles and verify healthy cellular activity towards configuring a new sensing technique. By interfacing between novel magnetoelectric materials and living brain cells, the project will constitute a fundamental scientific advance by elucidating the principles underlying the interface between responsive nanomaterials and biology towards realizing a new minimally invasive technology for direct imaging of neural activity with high relevance to human health. To meet these goals, the project builds on recent advances for synthesizing highly responsive nanofabricated magnetoelectric structures comprising cobalt ferrite (CFO) cores enveloped by piezoelectric barium titanate (BTO) shells for neural sensing and stimulation. The research trajectory consists of simulation, fabrication, and validation of responsive magnetoelectric nanostructures, and verification of growth and healthy function of living brain cells interfaced with these structures towards application of the technology for direct detection of biophysical events in tissue. The primary aims of the project include: (1) establishing new computational modeling and finite-element simulations to test optimal designs of CFO-BTO nanostructures interfaced with neurons; (2) nanofabrication of devices using novel nanometer scale electron-beam lithography and deposition technologies; (3) in vitro investigation of cell-device interface and signal transduction by combining state-of-the-art magnetic force microscopy methodologies, optical imaging and electrophysiology techniques. Specialized data acquisition routines and high-speed optical imaging techniques will be developed to quantify cell activity on optimized devices and relate it to magnetic and electrophysiological readouts. The development of injectable nanoscale agents for direct access to the brain at cellular scale is expected to transform the way we acquire brain signals and can help forge extraordinary advances in neuroscience and neurology. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-10

Indigenous communities have led scientific innovation by providing knowledge on medicinal plants, environmental impacts on health, and sustainable agriculture. Despite these important contributions that have been transformative to society, Indigenous scientists are under-represented in scientific research. In the US, Native Americans account for only 0.24% of master and doctoral students in the science, technology, engineering, and math fields even though Indigenous people make up 2.9% of the population. Of these Indigenous graduate students, only 25% will go on to complete their graduate degree. Several studies on the success of Native Graduate students have identified the critical factors for completion of a degree as mentorship, connection to community, and an emphasis on situatedness―the ability to connect self with environment, society, and culture. A major obstacle in the implementation of success-supporting factors is the lack of systemic infrastructure and studied interventions. This National Science Foundation Innovations of Graduate Education (IGE) Track 2 award supports the Center for Indigenous Research to Create Learning and Excellence (CIRCLE) at the University of Wisconsin-Madison. CIRCLE’s goal is to increase the number of Native American students who complete graduate degrees in STEM fields by developing, implementing, and studying a model of Indigenous science support. The development of CIRCLE has been led by Indigenous scientists and educators with a focus on Indigenous values of community, interdisciplinary approaches, and a strong sense of purpose. CIRCLE will focus first on mentorship training to create an environment that supports Indigenous graduate student development providing tools for conflict resolution and situatedness. The second focus of CIRCLE will be on developing a rigorous scientific community, that brings together Indigenous researchers and Tribal communities from different disciplines to cultivate innovation. Globally, the implementation of CIRCLE will provide a holistic approach for graduate student support that can be applied to all scientific training. A secondary impact of CIRCLE will be increasing the number of Indigenous scientists who will tackle challenges faced by Indigenous communities including the higher rates of exposure to environmental contaminants, metabolic disease, poverty, and a decreased lifespan of 20 years compared to the general population. The Innovations in Graduate Education (IGE) program is focused on research in graduate education. The goals of IGE are to pilot, test and validate innovative approaches to graduate education and to generate the knowledge required to move these approaches into the broader community. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-10

This project aims to serve the national need of mitigating the underrepresentation of women in science, and therefore contributes to scientific progress. Peer mentorship is one of the most effective avenues to increase the status of women in academia. By providing intense peer-mentorship to junior women scholars of international relations, the project will promote high-quality scholarship and contribute to an increased success of mentored women in academia. The project will promote these goals through the hosting of intense peer-mentorship workshops to foster networks, provide feedback and support, disseminate information, and encourage psychological resilience. The project also tracks the success of peer-mentorship programs through survey research and a collection of data on academic success. Studies that have evaluated the status of women in international relations over the past 30 years reveal significant gender gaps on numerous dimensions. The continued under-representation of female scholars at top research institutions and high ranks harms scientific progress. Recent research demonstrates that active mentoring, especially through workshops that foster networks, provide feedback and support, disseminate information, and encourage psychological resilience, are among the most promising avenues for change. The Journeys in World Politics workshop program has mentored young women scholars of International Relations (IR) since 2004. The project hosts annual three-day workshops that support 18-20 participants and includes research presentations by junior scholars, feedback from discussants, oral autobiographies by senior scholars, and career and gender discussion sessions involving topics such as networking, work-life balance, and navigating classroom gender dynamics. Beyond the workshops, the project maintains an active website and other forms of communication, arranges meetings at conferences, and thereby builds a broad network of women in the entire political science discipline. To track the success of mentorship workshops, the project collects more systematic data to evaluate the mechanisms through which mentoring programs increase long-term success rates for female political scientists. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-10

An organism’s ability to respond to its environment is fundamental to its survival. When the organism of interest is involved in a host-pathogen interaction, “the environment” becomes complex, including includes not only external forces, but also the conditions imposed by the interacting partner. There are also two genomes at play, each of which affects the behavior of both organisms. In addition, external environmental forces impose additional pressures, and each genome can affect how both partners respond. This project examines the role the host genome plays in altering behavior of both host and pathogen under environmental stress. It leverages an agriculturally relevant system, nematode infection of tomato. Parasitic nematodes are responsible for around $125 billion in annual crop loss worldwide with yield loss upwards of 80% for tomato. Limited control options are available, and the situation is exacerbated by an emerging concern in agriculture: the effect of warming nighttime temperatures (WNT). This unprecedented trend is causing critical challenges to crops. Broader, future impacts of this work include the development of novel approaches to examine host-pathogen interactions and how they are affected by external conditions. This then will lead to the identification of plant lines that are more resilient to both abiotic and biotic stresses. Importantly, by elucidating the molecular biology behind the parasite response to those plants under WNT, this study will go beyond merely identifying relevant host genes to contribute new insight into the mechanisms by which those genes alter the nematode biology. Understanding the nematode in addition to the plant paves the way towards targeting the parasite directly for crop improvement. The goals of this project align with an overarching concern in genetics: to identify DNA variants that influence how individuals respond to their environment. Here, the concept of “individuals” and “environment” are complex. DNA variants in one species will be identified that, in tandem with external environmental conditions, affect how another, interacting species responds. The environmental context considered is warming nighttime temperatures (WNT), a critical, highly relevant, and current environmental concern. Genetically variable tomato plants derived from a cross between a cultivated line and a wild line will be infected with a genetically homogeneous strain of parasitic nematodes. A control experiment will also be performed with uninfected plants. These early, late, and control experiments will be carried out under two temperature regimes: normal nighttime temperatures and WNT. For each treatment combination, phenotypes related to infection and plant health will be collected, along with gene expression data for both plant and nematode. With this design, connections between DNA variants in the tomato genome and molecular responses of the nematode as well as the plant will be made, and the effect of WNT on these connections will be uncovered through via a series of genetic mapping experiments. Leveraging the connections identified in this way, more complex genotype-expression-phenotype pathways can subsequently be inferred, providing a detailed view of the molecular biology of the plant-parasite interaction response to WNT. It will also pinpoint promising candidate genes, which will be functionally validated. All project outcomes will be made publicly accessible through publications and deposition of data and resources in long-term repositories. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-10

This project seeks to serve the national interest by developing learning theory crucial for guiding instructional transformation in undergraduate physiology towards principle-based reasoning. Many undergraduate science students leave science fields due to the perception of excessive memorization and lack of guidance on complex topics. Principle-based reasoning reduces reliance on memorization by supporting students’ use of fundamental principles and scientific reasoning when approaching complex problems. With approximately 650,000 students annually enrolled in introductory biology and 450,000 in anatomy & physiology across the nation, it's imperative to shift instruction towards conceptual understanding if we are to improve Science, Technology, Engineering, and Mathematics (STEM) education, increase retention of a diverse population of students and thus create a more diverse STEM workforce. The Physiology Principles project will build learning theory to characterize how students learn and coordinate science knowledge to develop principle-based reasoning. To capture a diverse range of student experiences, the project's investigators will pursue this research in introductory physiology courses that represent three important populations: pre-allied health majors at a community college, non-majors at a research-intensive institution, and biology majors at a residential liberal arts college within a research-intensive institution. As many of the students at these three institutions have career goals of becoming physician assistants, nurses, medical technologists, pharmacologists, physicians and other healthcare professionals, helping these students develop strong reasoning skills will enhance their abilities to solve the medical problems they encounter as well as be able to better explain the medical issue and prescribed treatments to the patient. This project will bring together students and researchers from Michigan State University, the University of Wisconsin, Madison and Waubonsee Community College to investigate how students develop principle-based reasoning, a rigorous form of mechanistic reasoning supported by metacognition and grounded in scientific principles. Specifically, the project team will develop learning theory that describes students’ conceptual development of flux and mass balance principle-based reasoning in introductory physiology courses; and the mechanisms of learning by which classroom practices framed by principles support the development of principle-based reasoning. To accomplish this, groups of students enrolled in the courses described above will be recorded during in-class discussions and interviewed across the semester. The project team will employ microgenetic learning analysis to adapt, revise and integrate coordination class theory and metacognition theory to develop a theory that proposes a mechanism for how physiology knowledge is organized and reorganized over time and how the contexts influence this learning. The project will expand the scope of coordination class theory to four contexts not previously studied: 1) students working in small groups during class, 2) students learning across an entire semester, 3) students learning Biology, and 4) students coordinating metacognitive epistemic resources with their conceptual knowledge resources. This project will also gather data about how each instructor incorporates these principles into how they teach and assess their class, as this will provide insight as to the role of the curriculum in supporting the development of principle-based reasoning. The project team will disseminate results from this project by publishing in relevant scholarly journals and presenting at regional and national STEM and discipline-based education conferences. The project team will also develop online modules for the American Physiology Society’s Center for Physiology Education to allow any faculty across the United States to access these resources as they prepare to and teach their courses. This project is supported by NSF’s EDU Core Research (ECR) program. The ECR program emphasizes fundamental STEM education research that generates foundational knowledge in the field. Investments are made in critical areas that are essential, broad and enduring: STEM learning and STEM learning environments, broadening participation in STEM, and STEM workforce development. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-10

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). As a society striving towards a clean energy future, integration of renewable energy sources is considered increasingly essential. The U.S. Energy Information Administration projects the share of renewables in the U.S. electricity generation to increase from 19% in 2019 to 38% in 2050. Most of the growth is attributed to wind and solar, which will account for nearly 80% of the renewables total in 2050. Due to their intermittency, energy storage is becoming critical. Battery energy storage systems are one of the fastest growing energy storage technologies due to their high energy densities, efficiency, and low self-discharge. To interconnect the DC batteries with the AC utility grid, power electronic converters are necessary. Such converters require that their building blocks (semiconductor switches, inductors, and capacitors) be rated for utility-scale specifications. Current commercial implementations feature a two/three-level converter with a transformer for voltage step-up function. Transformers are bulky, lossy, and costly. In contrast to these solutions, modular electronic converters have improved scalability, fault-tolerance, and reliability. This project focuses on a transformative design of a fundamental building block module to build an innovative, efficient, and power-dense DC-AC modular topology suitable for a battery energy storage system. The innovative feature of the proposed module is the three-phase integrated design, which enables high-density and efficient power conversion. The project also facilitates the involvement of undergraduate and high-school students through the deployment of learning tools and summer programs in power conversion to engage students from underrepresented communities. Existing modular topologies suffer from poor power density and low efficiencies which stem from their inherent converter design. They require additional components such as filters and/or DC-DC converters to overcome the low-quality waveforms imposed by the converter action. Literature studies indicate that these components can occupy 40%-80% of the converter volume and contribute to 50%-75% of the converter losses. The use of filters requires bulky capacitors, which are considered the weakest link and are detrimental to the system’s lifetime. The focal point of this project is the elimination of these components by focusing on an innovative design of the fundamental building block module. The first thrust of the project will aim to establish the fundamental and analytical theory of the proposed design including dynamic and steady-state models. These models will lay the groundwork to develop robust modulation and control methods for battery energy storage systems. Using the results from the first thrust, the project will deliver a laboratory-scale working prototype that demonstrates the highly scalable and modular design features. Further, the results will deliver detailed comparative studies to quantify the expected qualitative benefits in terms of efficiency and power density. The aim of the work is to lay the foundation of future ultra-dense and efficient class of modular power electronic converters. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-10

By collecting and storing genes from important wildlife now while these wildlife populations are under current threat of diminishment and possible extinction, current conservation practice can support efforts of future generations to restore these populations and/or explore them for potential benefits for the ecosystem. This project explores the proactive, large-scale storage of the genes of wildlife of cultural, conservation, and scientific significance. The approach seeks a unified mode for collecting, storing, and recording collections, based on a consultative process that honors the intentions, preferences, and priorities of local communities, including and especially Indigenous populations. The aims of the project include: 1) exploration of minimally-invasive sampling and storage of genetic samples from American red fox and American pine marten in the Great Lakes region; 2) evaluation of the generation of induced pluripotent cells (iPSCs) from these samples, a key technique to support species recovery; 3) evaluation of storage techniques (pooled-sample approaches) to reduce space and energy consumption; 4) execution of consultative engagements with communities, including Indigenous partners to evaluate the role of such technologies, if any, in local conservation planning, and to develop a unified system for recording and communicating collections, and 5) provision of training and instrumentation for communities to collect, process and store data for their own purposes, to assure self-determination. The project will conduct preliminary fieldwork to collect 15 minimally invasive genetic samples from red foxes (Vulpes vulpes) and American martens (Martes americana) in the Great Lakes Region. The samples will be used to identify technical gaps in generating induced pluripotent cells (iPSC) (i.e., reprogrammable cells that preserve genetic diversity) and to assess the coverage of genetic variation in the biosamples relative to the wild population. This proof-of-concept study will also identify technical gaps in long-term cryogenic preservation of biosamples and procedures to re-isolate single iPSC clones representing sampled individuals. We will further develop and deploy an ethical framework that honors Traditional Knowledge, Indigenous Data Sovereignty (IDS) principles, and public trust. The project will host a series of workshops, convening diverse publics from the Great Lakes region, including Sovereign Native Nations, to discuss and develop: 1) Data sovereignty principles as they apply to genetic material, 2) Governance guidelines for data sharing, storage and ownership of genetic information; 3) Training and infrastructure needs of communities and sovereigns related to genetic data management, 4) Biosampling decision making. Workshop results will include action plans for policy, training and educational needs, and guidelines for collaboration. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.